A study on the influence of molecular properties in the psychoactivity of cannabinoid compounds

Several molecular properties are calculated for a set of 26 cannabinoid compounds with the goal of connecting the psychoactivity of the compounds with an appropriate set of calculated properties. For this purpose we used quantum chemical (the AM1 semi-empirical method) and chemometric methods. The AM1 method was employed to calculate the set of quantum chemical molecular properties and the chemometric methods were employed with the aim of selecting the most relevant properties to be correlated with psychoactivity. The chemometric methods used were Principal Component Analysis (PCA), Hierarchical Cluster Analysis (HCA) and the K-Nearest Neighbor (KNN) method. The chemometric analysis showed that an electronic property (energy of LUMO), a hydrophobic property (log P), a steric property (volume of the substituent at the C4 position) and a topological property (Lovasz–Pelikan index) were the most important variables for the separation between the psychoactive and psychoinactive compounds. In order to validate our PCA, HCA and KNN results, eight new cannabinoid compounds (with known psychoactivity) were used in a prediction study and were classified correctly by the methods used in this work, indicating that our PCA, HCA and KNN models are able to predict reliable psychoactivity of cannabinoid compounds. Figure: ⁹-THC This revised version was published online in June 2005 with corrections to Table 1.     

Local molecular properties and their use in predicting reactivity

Expressions for the local electron affinity, electronegativity and hardness are derived in analogy to the local ionization energy introduced by Sjoberg, Murray and Politzer. The local polarizability is also defined based on an additive atomic orbital polarizability model that uses Rivail's variational technique. The characteristics of these local properties at molecular surfaces and their relevance to electrophilic aromatic substitution, to S_N2 reactivity and to the nucleophilicity of enolate ions are discussed.Figure The local ionization energy at the SES surfaces of methyl benzoate. The color scale ranges from 375 (blue) to 550 kcal mol^–1 (red). The blue areas are those for which interaction with an acceptor is most favorable.     

Prototropic tautomerism of imidazolone in aqueous solution: a density functional approach using the combined discrete/self-consistent reaction field (SCRF) models

A systematic investigation of the proton transfer in the keto-amino/enol tautomerization of imidazolone was undertaken. Calculations in aqueous solution were performed using both combined discrete/self-consistent reaction field (SCRF) and SCRF methods. Complexes containing one to three water molecules around the hydrophilic site of imidazolone were used for the combined discrete/SCRF calculations. The DFT results predict that the barrier height for non-water-assisted intramolecular proton transfer is very high (214.8 kJmol^–1). Hydrogen bonding between imidazolone and the water molecule(s) will dramatically lower the barrier by a concerted multiple proton transfer mechanism. The proton transfer process through a eight-member ring formed by imidazolone and two water molecules is found to be more efficient and the calculated barrier height is ca. 61 kJmol^–1.Figure DFT calculations in aqueous solution predict the H-bonding between imidazolone(IZ) and the water molecule(s) will dramatically lower the tautomeric barrier by a concerted multiple proton transfer mechanism, in which an eight-member ring structure formed by IZ and 2H₂O is found to be more efficient and the barrier is 60.8 kJ mol^–1, much less than 214.8 kJ mol^–1 in the non-water-assisted mechanism.     

Decomposition mechanism of 3-<Emphasis Type="Italic">N</Emphasis>-morpholinosydnonimine (<Emphasis Type="Bold">SIN-1</Emphasis>)—a density functional study on intrinsic structures and reactivities

Selected intrinsic aspects of the mode of action of 3-N-morpholinosydnonimine (SIN-1) and its follow-up products are investigated by means of density functional theory. Besides the well known radical-cationic Feelisch–Schoenafinger pathway, an alternative anionic route via a neutral radical is proposed and included in the study. The individual reaction pathways are followed. Most notably, the overall activation barrier for the cationic route is calculated to be 184.04 kcal mol^–1, while the one for the anionic route is predicted to be more favorable with 14.09 kcal mol^–1.Figure A mere conformational change is predicted by DFT theory to elicit NO ejection from the SIN-1a radical cation, formed after one electron oxidation of the N-nitrosohydrazine SIN-1a.

A new visualization scheme of chemical energy density and bonds in molecules

Covalent bond describes electron pairing in between a pair of atoms and molecules. The space is partitioned in mutually disjoint regions by using a new concept of the electronic drop region R_D, atmosphere region R_A, and the interface S (Tachibana in J Chem Phys 115:3497–3518, 2001). The covalent bond formation is then characterized by a new concept of the spindle structure. The spindle structure is a geometrical object of a region where principal electronic stress is positive along a line of principal axis of the electronic stress that connects a pair of the R_Ds of atoms and molecules. A new energy density partitioning scheme is obtained using the Rigged quantum electrodynamics (QED). The spindle structure of the stress tensor of chemical bond has been disclosed in the course of the covalent bond formation. The chemical energy density visualization scheme is applied to demonstrate the spindle structures of chemical bonds in H₂, C₂H₆, C₂H₄ and C₂H₂ systems.Figure Field theory of the energy density.     

Effect of Pt and Sn on the adsorption of n-heptane in γ-Al2O3 catalyst models

The Grand Canonical Monte-Carlo (GCMC) method has been used to carry out simulations of the adsorption of n-heptane in models of naphtha-reforming catalysts. Models used in the study differed in the number and distribution of metal atoms—Pt and Sn. The number of adsorbed n-heptane molecules grows linearly with increasing number of metal atoms. The effect of Pt content on the adsorption of n-heptane molecules is most distinct at approximately 100 kPa and within the lower range of the temperatures investigated. In the models of bimetallic catalysts, the effect of the two metals is additive.Figure Effect of Pt and Sn on number of n-heptane molecules adsorbed in Al₂O₃ catalyst in 773 K and 1000 kPa.      

An unusual feature of end-substituted model carbon (6,0) nanotubes

We have examined the effects of substituents on the computed electrostatic potentials V_S(r) and average local ionization energies on the surfaces of model carbon nanotubes of the types (5,5), (6,1) and (6,0). For the (5,5) and the (6,1), the effects upon both V_S(r) and of substituting a hydroxyl group at one end are primarily localized to that part of the system. For the (6,0) tube, however, a remarkable change is observed over its entire length, with V_S(r) showing a marked gradation from strongly positive at the substituted end to strongly negative at the other; correspondingly goes from higher to lower values. Replacing OH by another resonance- donor, NH₂, produces similar results in the (6,0) system, while the resonance withdrawing NO₂ does the opposite, but in equally striking fashion. We explain these observations by noting that the arrangement of the C–C bonds in the (6,0) tube facilitates charge delocalization over the full length and entire surface of the tube. Substituting NH₂ and NO₂ at opposite ends of the (6,0) tube greatly strengthens the gradations in both V_S(r) and The first hyperpolarizability of this system was found to be nine times that of para-nitroaniline, suggesting possible nonlinear optical applications.Figure HF/STO-5G electrostatic potential on outer surface of open (6,0) C₇₂H₁₀NH₂NO₂. The nitro group is at the right end of the tube, the amino group at the left. In eV: purple is less than 14, blue is between 14 and 15, green is between 15 and 16.5, yellow is between 16.5 and 17.5, and red is more than 17.5.      

Hydrogen-bond effects on the electronic absorption spectrum and evaluation of nonlinear optical properties of an aminobenzodifuranone derivative that exhibits the largest positive solvatochromism

In this work, for the first time, a theoretical approach to describing the influence of hydrogen-bond formation on the electronic absorption spectrum and nonlinear optical properties of an aminobenzodifuranone derivative (ABF) that exhibits the largest positive solvatochromic shift compared to other known chromophores is given. The solvent effect was included via the supermolecule (SM) method. The calculations were performed for a strong low-lying (^*) transition based on the configuration interaction singles (CIS) and time-dependent DFT (TDDFT) methods. The first-order hyperpolarizabilities () were computed using the finite-field (FF) technique combined with the Hartree–Fock (HF) theory. Reasonable agreement between theory and experiment was obtained for the solvatochromic shifts of the ABF molecule. Moreover, it was found that H-bond formation strongly influences the NLO response of the systems investigated.Figure The interaction difference-density maps of the systems studied: a II - complex ABF with NFTB; b III - complex ABF with HMPA. The red color designates an increase of the electron density caused by the intermolecular interactions, whereas blue indicates a corresponding decrease of the electron density. The isodensity contours were plotted for ±0.01 electron/bohr³ (DFT/B3LYP/6-31G(d,p)).     

Organization of rhodopsin molecules in native membranes of rod cells–an old theoretical model compared to new experimental data

It has been shown that rhodopsin forms an oligomer in the shape of long double rows of monomers. Because of the importance of rhodopsin as a template for all G protein-coupled receptors, its dimeric, tetrameric and higher-oligomeric structures also provide a useful pattern for similar structures in GPCRs. New experimental data published recently are discussed in the context of a proposed model of the rhodopsin oligomer 1N3M deposited in the protein data bank. The new rhodopsin structure at 2.2 Å resolution with all residues resolved as well as an electron cryomicroscopy structure from 2D crystals of rhodopsin are in agreement with the 1N3M model. Accommodation of movement of transmembrane helix VI, regarded as a major event during the activation of rhodopsin, in a steady structure of the oligomer is also discussed.Figure Superimposition of the 1U19 (red wire), 1GZM (purple wire) and 1N3M (blue wire) rhodopsin structures. Size of the wires is proportional to thermal factors of backbone C atoms, view parallel to the membrane.      

On the nature of bonding in HCOOH...Ar and HCOOH...Kr complexes

The chemical interaction in HCOOH...Ng (Ng=Ar, Kr) complex was analyzed by topological analysis of the electron density based on Atoms-In-Molecules theory. For all computationally stable equilibrium structures of 1:1 HCOOH...Ng complexes, an intermolecular bond path with a bond critical point was found and perturbation of formic acid (FA) atomic basins and electron density was observed. The intermolecular interaction between the two complex subunits can be classified, according to its nature, as a closed-shell van der Waals type of interaction. However, one of the computed structures (complex II), pictures a noble gas atom attached linearly to the acidic O–H tail of FA. In this particular case, the electron density at the intermolecular bond critical point was found to resemble a hydrogen-bonded system and thus, may be termed a hydrogen-bond-like interaction. This change in the nature of the interaction is also shown by large perturbations of the FA properties found for this complex structure. The structural and vibrational perturbations are larger than for the other three structures and they increase for the Kr complexes compared to the Ar complex.Figure Electron density analysis of HCOOH...Ng (Ng=Ar,Kr) complex.     

Computer simulation of polypeptide translocation through a nanopore

A simplified model of polypeptide chains was designed and studied by means of computer simulations. Chains were represented by a sequence of united atoms located at the positions of the -carbons. A further assumption was the lattice approximation for the chains. We used a (310) lattice, which was found useful for studying properties of proteins. The force field used consisted of a long-range contact potential between amino-acid residues and a local preference for forming -helical states. The chain consisted of two kinds of residues: hydrophilic (P) and hydrophobic (H) ones forming model helical septets –HHPPHPP– in a sequence. The chains were placed near an impenetrable surface with a square hole in it. The size of the hole was comparable or smaller than the size of a chain. The properties of these model chains were determined using the Monte-Carlo simulation method. During the simulations, translocation of the chain through the hole in the wall was observed. The influence of the chain length, the temperature differences on both sides of the wall and the force field on the chain properties were investigated. It was shown that the translocation time scales as N^2.2 and it was found that the presence of the local helical potential significantly slows down the process of translocation.Figure: The snapshots of typical chains conformation obtained during the simulation for chain consisted of N = 60. The values of the local potential _loc = -8.     

Molecular dynamics simulation of hepatitis C virus IRES IIId domain: structural behavior,electrostatic and energetic analysis

The dynamic behavior of the HCV IRES IIId domain is analyzed by means of a 2.6-ns molecular dynamics simulation, starting from an NMR structure. The simulation is carried out in explicit water with Na⁺ counterions, and particle-mesh Ewald summation is used for the electrostatic interactions. In this work, we analyze selected patterns of the helix that are crucial for IRES activity and that could be considered as targets for the intervention of inhibitors, such as the hexanucleotide terminal loop (more particularly its three consecutive guanines) and the loop-E motif. The simulation has allowed us to analyze the dynamics of the loop substructure and has revealed a behavior among the guanine bases that might explain the different role of the third guanine of the GGG triplet upon molecular recognition. The accessibility of the loop-E motif and the loop major and minor groove is also examined, as well as the effect of Na⁺ or Mg²⁺ counterion within the simulation. The electrostatic analysis reveals several ion pockets, not discussed in the experimental structure. The positions of these ions are useful for locating specific electrostatic recognition sites for potential inhibitor binding. Figure Superposition of 14 structures representative of the evolution of IRES IIId RNA along 2.6-ns MD simulation     

Effects of shape,size, and pyrene doping on electronic properties of graphene nanoflakes

Effects of size, shape, and pyrene doping on electronic properties of graphene nanoflakes (GNFs) were theoretically investigated using density functional theory method with PBE, B3PW91, and M06-2X functionals and cc-pVDZ basis set. Two shapes of zigzag GNFs, hexagonal (HGN) and rhomboidal (RGN), were considered. The energy band gap of GNF depends on shape and decreases with size. The HGN has larger band gap energy (1.23–3.96 eV) than the RGN (0.13–2.12 eV). The doping of pyrene and pyrene derivatives on both HGN and RGN was also studied. The adsorption energy of pyrene and pyrene derivatives on GNF does not depend on the shape of GNFs with energies between 21 and 27 kcal mol^?1. The substituent on pyrene enhances the binding to GNF but the strength does not depend on electron withdrawing or donating capability. The doping by pyrene and pyrene derivatives also shifts the HOMO and LUMO energies of GNFs. Both positive (destabilizing) and negative (stabilizing) shifts on HOMO and LUMO of GNFs were seen. The direction and magnitude of the shift do not follow the electron withdrawing and donating capability of pyrene substituents. However, only a slight shift was observed for doped RGN. A shift of 0.19 eV was noticed for HOMO of HGN doped with 1-aminopyrene (pyNH₂) and of 0.04 eV for LUMO of HGN doped with 1-pyrenecarboxylic acid (pyCOOH).

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Graphical Abstract HOMO and LUMO Energies of pyrene/pyrene derivatives doped Graphene Nanoflakes

     

Theoretical potential scans and vibrational spectra of vinyl selenonyl halides CH2=CH–SeO2X (X is F, Cl and Br)

The structure and conformational stability of vinyl selenonyl fluoride, chloride and bromide CH₂=CH–SeO₂X (X is F, Cl and Br) were investigated using density functional B3LYP/6-311+G** and ab initio MP2/6-311+G** calculations. From the calculations the molecules were predicted to exist only in the non-planar gauche conformation with the vinyl C=C group almost eclipsing one of the selenonyl Se=O bonds as a result of conjugation between the two moieties. Single-minimum potential scans were calculated at the DFT level for the molecules. The vibrational frequencies were computed using B3LYP/6-311+G**. Normal coordinate calculations were then carried out and potential energy distributions were calculated for the three molecules in the gauche conformation.Figure Potential function for the asymmetric torsion in vinyl selenonyl fluoride (dotted line), chloride (dashed line) and bromide (solid line) as determined at the DFT-B3LYP/6-311+G** level     

Structure and dynamics of Candida rugosa lipase: the role of organic solvent

The effect of organic solvent on the structure and dynamics of proteins was investigated by multiple molecular dynamics simulations (1 ns each) of Candida rugosa lipase in water and in carbon tetrachloride. The choice of solvent had only a minor structural effect. For both solvents the open and the closed conformation of the lipase were near to their experimental X-ray structures (C rms deviation 1–1.3 Å). However, the solvents had a highly specific effect on the flexibility of solvent-exposed side chains: polar side chains were more flexible in water, but less flexible in organic solvent. In contrast, hydrophobic residues were more flexible in organic solvent, but less flexible in water. As a major effect solvent changed the dynamics of the lid, a mobile element involved in activation of the lipase, which fluctuated as a rigid body about its average position. While in water the deviations were about 1.6 Å, organic solvent reduced flexibility to 0.9 Å. This increase rigidity was caused by two salt bridges (Lys85–Asp284, Lys75–Asp79) and a stable hydrogen bond (Lys75–Asn 292) in organic solvent. Thus, organic solvents stabilize the lid but render the side chains in the hydrophobic substrate-binding site more mobile. Figure Superimposition of open (black, PDB entry 1CRL) and closed (gray, PDB entry 1TRH) conformers of C. rugosa lipase. The mobile lid is indicatedThis revised version was published online in October 2004 with corrections to the Graphical Abstract.     

Reinvestigation of molecular structure and barrier to internal rotation of pyridinium N-phenolate betaine dye

In the present paper, the results of a systematic theoretical study of the molecular structure of 4-(1-pyridinium-1-yl)phenolate betaine are reported. The ground-state molecular structure and the barrier to internal rotation of the betaine dye molecule were calculated ab inito (with Hartree–Fock theory and the second-order of Möller–Plesset method) and with density functional theory (DFT). In order to estimate the complete basis set limit, the calculations of barriers to internal rotations were performed using correlation–consistent basis sets with a maximal cardinal number of four. It was determined that electron correlation is crucial in order to obtain reliable geometries and rotational barriers of the molecule investigated. For the sake of comparison, the results of calculations using the AM1 Hamiltonian are also presented.Figure Investigated betaine dye.     

Symmetry breaking in charge-transfer compounds. The effects of electric fields and substituents on the properties of bipyrazine cations

The effects of an electric field and of various substituents on the symmetry breaking of degenerate near-midgap orbitals and on different properties in bi-N,N-pyrazine-1,6-hexatriene dications ([C₄N₂H₄—(CH)₆—C₄N₂H₄]²⁺) are investigated by means of semiempirical PM3 and INDO CI methods. The electric field is simulated by applying positive/negative point charges at varying distances from the end-points, and the substitutions are done with single chlorine atoms or with CN, OH or CH₃ groups, at various positions along the chain or on one of the pyrazine rings. The results are compared with calculations on the unsubstituted, field-free system. It is found that an electric field (e.g., as applied over a membrane) leads to significant symmetry breaking and also polarizes the HOMO and LUMO, such that electron transfer between these orbitals generates large dipole-moment shifts and non-negligible oscillator strengths. With substituents, no major symmetry breaking is observed for the ground state. Instead, strong modifications of the orbital picture are observed, in particular when using the stronger electron-withdrawing substituents. Placing the substituent in a ring position does, furthermore, lead to the possibility of large charge transfer.     

ProPose: a docking engine based on a fully configurable protein–ligand interaction model

Virtual high-throughput screening of molecular databases and in particular high-throughput protein–ligand docking are both common methodologies that identify and enrich hits in the early stages of the drug design process. Current protein–ligand docking algorithms often implement a program-specific model for protein–ligand interaction geometries. However, in order to create a platform for arbitrary queries in molecular databases, a new program is desirable that allows more manual control of the modeling of molecular interactions.For that reason, ProPose, an advanced incremental construction docking engine, is presented here that implements a fast and fully configurable molecular interaction and scoring model. This program uses user-defined, discrete, pharmacophore-like representations of molecular interactions that are transformed on-the-fly into a continuous potential energy surface, allowing for the incorporation of target specific interaction mechanisms into docking protocols in a straightforward manner. A torsion angle library, based on semi-empirical quantum chemistry calculations, is used to provide minimum energy torsion angles for the incremental construction algorithm. Docking results of a diverse set of protein–ligand complexes from the Protein Data Bank demonstrate the feasibility of this new approach.As a result, the seamless integration of pharmacophore-like interaction types into the docking and scoring scheme implemented in ProPose opens new opportunities for efficient, receptor-specific screening protocols. Figure ProPose — a fully configurable protein-ligand docking program — transforms pharmacophores into a smooth potential energy surface.This revised version was published online in October 2004 with corrections to the Graphical Abstract.     

Structure of glutathione S-transferase of the filarial parasite Wuchereria bancrofti: a target for drug development against adult worm

A three dimensional structural model of Glutathione-S-transferase (GST) of the lymphatic filarial parasite Wuchereria bancrofti (wb) was constructed by homology modeling. The three dimensional X-ray crystal structure of porcine -class GST with PDB ID: 2gsr-A chain protein with 42% sequential and functional homology was used as the template. The model of wbGST built by MODELLER6v2 was analyzed by the PROCHECK programs. Ramachandran plot analysis showed that 93.5% of the residues are in the core region followed by 5.4 and 1.1% residues in the allowed and generously allowed regions, respectively. None of the non-glycine residues is in disallowed regions. The PROSA II z-score and the energy graph for the final model further confirmed the quality of the modeled structure. The computationally modeled three-dimensional (3D) structure of wbGST has been submitted to the Protein Data Bank (PDB) (PDB ID: 1SFM and RCSB ID: RCSB021668). 1SFM was used for docking with GST inhibitors by Hex4.2 macromolecular docking using spherical polar Fourier correlations.Figure: A three-dimensional (3D) structure of Glutathione-S-transferase (GST) of the lymphatic filarial parasite Wuchereria bancrofti (wb) was constructed by homology modeling. This modeled 3D structure of wbGST has been submitted to the Protein Data Bank (PDB) (PDB ID: 1SFM and RCSB ID: RCSB021668).     

Electrostatics of Cytochrome-c assemblies

Electrostatic potentials along with computational mutagenesis are used to obtain atomic level insights into Cytochrome-c in order to design efficient bionanosensors. The electrostatic properties of wild type and mutant Cytochrome-c are examined in the context of their assembly, i.e. are examined in the absence and presence of neighboring molecules from the assembly. An intense increase in the positive potential ensues when the neighboring molecules are taken into account. This suggests that in the extrapolation of electric field effects upon the design of assemblies, considering the properties of only the central molecule may not be sufficient. Additionally, the influence of the uncharged residues becomes quite diminished when the molecule is considered in an assembly. This could pave the way for making mutants that might be more soluble in different media used in the construction of devices.FigureThe electrostatic potential, calculated using the program DELPHI [20] mapped on to the surface of Cytochrome-c when it is considered by itself (in the left column) and in the presence of the electrostatic field generated by the presence of the surrounding 4 molecules on the right (see Fig. 3). The potentials range from –10kT in red to +10kT in blue. The central figure shows the regions that have been mutated to positively charged residues by placing a unit positive charge at the terminal atom of the respective side chain. The figures range from the wild type in the first row, followed by the Gln12, Asn70, Asp50, Glu90 and Ala83 mutants.